Hemicholinium related lipids are new synthetic, biologically active compounds. (R. D. Gandour and G. Kumaravel, LSU, U.S. Pat. No. 5,196,418). These compounds inhibit protein kinase C, (G. Kumaravel, C. L. Ashendel and R. D. Gandour, J. Med. Chem. 1993, 36, 177) inhibit aggregation of erythrocytes by clusterin or fibrinogen, [I. B. Fritz, K. Burzdy and R. D. Gandour, Workshop on Clusterin (Pembroke College, Cambridge, UK, 13-16, September 1992) 21; K. Burdzy, R. D. Gandour and I. B. Fritz, Workshop on Clusterin (Pembroke College, Cambridge, UK, 13-16, September 1992) 22] and potently kill sperm and other cells. These cationic lipids structurally resemble the aryl hemicholiniums, which inhibit acetylcholine synthesis by blocking the uptake of choline, [F. C. Macintosh, R. I. Birks and P. B. Sastry, Nature (London), 1956, 178, 1181; J. E. Gardiner, Biochem. J., 1961, 81, 297; P. Guynet, J. Bossier, J. Beaujouan and J. Glowinski, Brain Res., 1973, 62, 523; L. A. Smart, J. Med. Chem., 1983, 26, 104] serve as substrates for choline acetyltransferase, [B. Collier, and F. G. Macintosh, Canad. J. Physiol. Pharmocol., 1969, 47, 127; B. A. Hemsworth, Eur. J. Pharmacol., 1971, 15, 91; S. M. Shreeve, G. B. Veitch and B. A. Hemsworth, J. Med. Chem., 1984, 27, 754] and inhibit acetylcholine esterase. [B. H. Lee, T. C. Stelly, W. J. Colucci, J. G. Garcia, R. D, Gandour, and D. M. Quinn, Chem. Res. Toxicol., 1992, 5, 411].
Acyltransferases regulate many steps in the synthesis and the metabolism of lipids. Cells require lipid synthesis to produce components of membranes, and cells employ lipid metabolism as an alternative source of energy to glucose metabolism. Inhibitors of various enzymes in both these pathways find use as potential therapeutic agents or biocides or both. Hemipalmitoyl carnitinium (HPC), structural analogue of hemicholinium lipids, potently inhibits carnitine palmitoyltransferase (CPT), [Gandour, R. D. Leung, O. -t.; Greway, A. T.; Ramsay, R. R.; Nic a' Rhaird, N.; Fronczek, F. R.; Bellard, B, M.; Kumaravel, G., J. Med. Chem., 1993, 35, 237-242] which many believe is the rate-limiting step for hepatic mitochondrial .beta.-oxidation of long-chain fatty acids. CPT activity usually increases under certain conditions, e.g., starvation and diabetes, resulting in higher levels of fatty-acid oxidation and ketogenesis. CPT inhibitors (e.g., 2-tetradecylglycidyl-CoA and amino- and palmitoylaminocarnitine) decrease blood ketone and blood glucose concentrations in vivo, suggesting that CPT inhibitors can aid in alleviating the diabetic syndrome.
Molecular modeling studies suggest that an eight-membered ring is a better match than a six-membered ring to the putative reaction intermediate for all acyltransferases. The cholinium phosphorus cycles are potential analogs of phosphatidyl choline. The compound shown below shows antimicrobial activity. See CA 109 (19): 170548w, CA 85 (12): 80050j.
Similar compounds have been prepared where R is a shorter chain length and includes aryl and where the group attached to the nitrogen atom is alkyl or phenyl. These compounds have proven to exhibit anticholinesterase activity. See CA 81 (19): 11648j, CA (5): 43448h.
Accordingly, there is a need for more potent inhibitors of all acyltransferases.